The effective use of nitroimidazole hypoxic cell sensitizers as adjuncts to radiotherapy in the clinic is limited by neurotoxic side effects. The overall objective of the project is to evaluate several radiosensitizers which are either in chemical use or are potential candidates for this purpose in order to select the least neurotoxic agent and thereby increase the potential therapeutic ratio. We have determined the toxicity, pharmacokinetics and relative neurotoxicity (using quantitative functional tests of locomotor co-ordination and balance and high frequency hearing loss) of Misonidazole, Ro-05-9963, Ro-07-0741, SR 2508, SR 2555 and Metronidazole in the mouse. The relative neurotoxicity of these sensitizers is 1.0, 1.6, 0.3, 5.0, is greater than 6.0 and 2.4 respectively. Studies are in progress to determine the magnitude of the exposure dose for neurotoxicity, the lows and development of the specific neurotoxic lesions induced by misonidazole and other sensitizers and to evaluate the relative contribution made by electron-affinity and lipophilicity. Our current research goals include (1) the development of a screening system to assess changes in neuronally-associated proteins or enzymes (2) to determine changes in the levels of reducing equivalents or the redox balance of nervous tissue exposed to the chronic administration of sensitizers and (3) to evaluate the use of protective agents against sensitizer neurotoxicity and how this relates to mechanism(s).